DNA Binding Polyamides in Biological Systems

Abstract

Small molecules that bind selectively to a DNA sequence in the human genome are potentially useful tools for molecular biology and human medicine. Polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) are small molecules that bind DNA according to a set of pairing rules with affinities and specificities that rival natural transcription factors. By directly competing with a given transcription factor or other DNA binding protein for its binding site, polyamide can cause inhibition of diverse biological processes, such as retroviral integration and gene transcription. Polyamides are presented which inhibit the in vitro integration activities for two retroviruses, M-MuLV and HIV-l. Polyamides are described that inhibit TBP binding to the HER2 promoter, a gene implicated in human breast cancer. Failure to achieve inhibition of HER2 transcription in cell culture led to the surprising discovery that polyamide-fluorescent dye conjugates are cell permeable, but that nuclear localization does not occur in many cell lines. Efforts toward modified polyamides with enhanced nuclear localization properties are presented. In order to extend the number of sequences amenable to high affinity recognition, alteration of the C-terminal polyamide has been investigated. The development of conditions for polyamide solid-phase synthesis on a new resin, which allows for the generation of truncated tail polyamides, is presented. During the original route to one of these compounds, an unexpected reaction was uncovered that leads to entirely different C-terminal tails.